New functions of elongation factor eEF1A2 in the formation of filopodia: from neurons to cancer cells

Trabajo presentado en Barts Cancer Institute seminars, celebrados en Londres (Inglaterra) el 15 de marzo de 2018.Reorganization of the actin cytoskeleton and new local synthesis of proteins are two processes essential for filopodia formation. Filopodia have an important role in cell migration, neurite outgrowth and serve as precursors for dendritic spines in neurons. Actin-binding proteins play crucial roles in regulating actin dynamics. The reorganization of the actin cytoskeleton mediates many of the structural changes induced by neuronal activity as well as the development of invasive structures like lamellipodia and filopodia in cancer cells. The essential elongation factor eEF1A was first isolated as an actin-binding protein. This factor displays two very similar forms in vertebrates, eEF1A1 (A1) and eEF1A2 (A2), which share 92% sequence identity. While the first is expressed throughout life in almost all tissues, the second form is specific to brain and skeletal muscle pointing to specific roles of eEF1A2 in tissues where cellular and/or subcellular plasticity is most relevant. Interesting, overexpression of isoform A2, but not isoform A1, has been detected in many tumor tissues. The work of our group has focused on the role of isoform switch in synaptic plasticity and, more specifically, in the physiological relevance of phosphorylation events at fourth serine residues specifics of isoform A2 and located in the third domain. Our functional analysis in hippocampal neurons shows that phosphorylation increases significantly formation of filopodia and dendritic spines. Moreover, actin dynamics and consequently filopodium motility are clearly enhanced in neurons transfected with phospho-mimetic mutants. On the other hand, mass spectrometry analysis of breast cancer cell line fractions has shown an enrichment of isoform A2 in protrusions compared to cell-bodies (Mardakheh F et al. Dev Cell, 2015). In summary all these data suggest that isoform A2 could be required to enhance filopodia formation and motility. The comparison by mass spectrometry analysis of filopodia components and phosphoproteome from neurons and cancer cell lines will help us to better understand the molecular mechanisms involved in the formation of these protrusions that have a crucial role in cellular migration and synaptic plasticity